Hemorrhoids is one of the rectal pathologies with the highest worldwide incidence, having a prevalence rate of 4% in the United States and United Kingdom (Johanson J F, Sonnenberg A. The prevalence of hemorrhoids and chronic constipation, an epidemiological study. Gastroenterology 1990; 98:380). Hemorrhoids are abnormally swollen veins in the rectum and anus. Hemorrhoids are abnormally large or symptomatic conglomerates of blood vessels, supporting tissues, and overlying mucous membrane or anorectal skin venous swelling of the venous plexus of the rectal or anus mucous. It is called internal hemorrhoids when the upper plexus veins are damaged; they are located over the anal canal and are covered with mucous. The lower plexus veins are located below the region where anus and rectum converge and are covered with external skin. The drainage system of this zone lacks valves and for this reason the erect position of man rises pressure inside hemorrhoid veins, predisposing condition to hemorrhoidal disease. A complication of hemorrhoid may be produced due to its strangulation that develops a dark color as a result of underlying thrombosis.
There are many formulations in the form of suppositories or rectal ointments for local application, for the treatment of this pathology. These preparations contain anesthetics, anti-inflammatory, or anti-itching, such as ERCAL, SHERIPROCT, ULTRAPROCT, XYLOPROCT, PROCTAXID, PROCTOGLYVENOL (Rosenstein E. Pharmaceutical specialty Dictionary. Fortieth first edition 1995, 778, 1539, 1730, 1798, 1437, 1436). The main action of aforementioned formulations is a decrease in swelling and reduction of pain.
Different clinical studies have been currently carried out using vasodilators (topical nifedipine and anticoagulants such as heparin cream, which have shown some effectiveness and adverse events in the treatment of this disease (Perrofti P, Antropoli C, Molino D, De Stefano G, Antropoli M. Conservative treatment of acute thrombosed external hemorrhoids with topical nifedipine, (Dis Colon Rectum 2001 44(3):405-409)).
Besides, there are other treatments that are used in hemorrhoids (grade I and II) such as sclerosant injections, photocoagulation, hemorrhoidectomy, cryosurgery and LASER. But these treatments also have disadvantages since specialized personnel and equipment are required and attendance to medical centers is obligatory.
Sometimes complications may occur in grade III and IV hemorrhoids because of thrombosis (acute hemorrhoidal disease) and the above mentioned drugs and treatments do not cure this pathology, being necessary to remove the thrombi by means of surgery (Thrombectomy) (Bleday R, Breen E. Clinical Features of hemorrhoids. Sabiston. Textbook of surgery 16 edition, 2001: 980-986). This operation in acute phase produces a lot of discomfort and inconveniences which affect the patient's quality of life, as well as some risks of post-operation complications (Goldman: Cecil Textbook of medicine 21st Ed., Chapter 143—Diseases of the rectum and anus 570-572).
A non-surgical treatment of acute hemorrhoid disease would be very advantageous since it would avoid all the above-described inconveniences, even in those cases where hemorrhoidectomy would be needed, since this type of treatment would allow the patient to undergo surgery with a better quality of life and less complications.
Thrombolytic agents have the ability to lyse thrombi and restore venous flow in the anal canal, which would be possible using agents such as tissue-type plasminogen activator (t-PA), urokinase (u-PA) and streptokinase (SK), because of its thrombolytic and anti-inflammatory effect. Mechanism of action of each one these agents is different, in the case of t-PA, ternary complex is formed with the fibrin in the clot and plasminogen, causing the activation of plasminogen that is converted into plasmin, which is the enzyme responsible for the lysis of blood clots. (Zamarron C, Lijnen H R, Collen D. Kinetics of the activation of plasminogen by natural and recombinant tissue-type plasminogen activator, J Biol Chem, 1984; 259: 2080-2083); In the case of u-PA, it is a proteolytic enzyme that acts directly on plasminogen which is responsible for fibrin clot degradation achieving thrombolytic effect (Schneider P, Bachmann F, Sauser D. Urokinase: a short review of its properties and of its metabolism. In D'Angelo A, de. Urokinase: basic and clinical aspects. London: Academic Press, 1982; 1-15). t-PA and u-PA have been used as fibrinolitic in some diseases of thrombotic origin like pulmonary embolism, deep vein thrombosis, and others by parenteral administration. (Ouriel K, Veith F J. Acute lower limb ischemia: determinants of outcome, Surgery 1998; 124:336-342 109); (Manteiga R, Souto C, Altés A, et al. Short-.course thrombolysis the first line of therapy for cardiac valve thrombosis, J Thorac Cardiovasc Surg 1998; 115:780-784). Recombinant Streptokinase (rSK) pharmacologyc effect, the same as natural SK, is the fibrinolisys activation, where the final pass in fibrinolityc cascade is the formation of plasmin increasing fibrinogen product degradation (Chesebro J H, Knatterud G, Roberts R, et al. Thrombolysis in myocardial infarction (TIMI) Trial, Phasek. A comparison between intravenous tissue plasminogen activator and intravenous Streptokinase. Clinical Findings through hospital discharge. Circulation 1987; 76:142-154).
The anti-inflammatory effects are due to the enzymatic transformation of plasminogen into plasmin cleaving fibrinogen, fibrin or both, located in inflamed zone or in the clot favoring their drainage and diminishing the inflammation and edema (Rosenstein E. Pharmaceutics specialty Dictionary de. Fortieth first edition 1995, 778, 1539, 1730, 1798, 1437, 1436). Therefore a combination in a formulation of more than one thrombolytic agent or the combination of this agent with anti-inflammatory could be obtained a better efficacy in thrombotic disease like acute hemorrhoidal disease.
Streptokinase is high molecular weight protein which nowadays is using for the treatment of acute myocardial infarction, deep vein thrombosis, permanent vascular access thrombosis and other disease with thrombotic origin. In this way is presented in different pharmaceutics form like lyophilized for parenteral use. Also it has also been used for mucosal administration, for example, VARIDASE, for edema relieve of inflammatory process or in orally administered pills. It has also been reported rectal administration with the main objective of systemic action for the treatment of hematoma re-absorption or just for comparing its concentration in the blood after rectal and oral administration (Oliven A, Gidron E. Orally and rectally administered Streptokinase. Investigation of its absorption and activity, Pharmacology 1981; 22(2): 135-138); (de Boer A G, Moolenaar F, de Leede L G, Breimer D D. Rectal drug administration: Clinical pharmacokinetic considerations, Clin Pharmacokinet 1982; 7(4): 285-311).
The use of rectal formulation mentioned in this invention which has thrombolytic agents for the treatment of acute hemorrhoidal disease, is very convenient for treating this pathology locally, it is non invasive, not painful and without complication for the patient, due to the capacity of eliminating the thrombi and inflammation of the affected zone.